Dr. Rita Kalyani is a junior faculty member in the Division of Endocrinology and Metabolism at the Johns Hopkins School of Medicine where her clinical practice is dedicated to the prevention and treatment of diabetes. She previously completed a Masters of Health Science in Clinical Investigation at the Johns Hopkins School of Public Health where she applied her training in epidemiology and study design to characterize the association of diabetes with disability in routine physical tasks. With the support of this Mentored Career Development Award (CDA), Dr. Kalyani seeks to establish the role of dysglycemia and/or insulin resistance (IR) in accelerated muscle loss and the role of current diabetes treatment modalities such as exercise or insulin-sensitizing medications in mitigating these effects. She also aims to better characterize skeletal muscle mitochondrial dysfunction in type 2 diabetes as a pathway connecting IR with subsequent loss of muscle mass and strength. Dr. Kalyani will (1) enhance her research knowledge and skills with training in clinical translatio research including: trial management, biostatistics, gerontology, body composition assessment, skeletal muscle physiology, and hyperinsulinemic-euglycemic clamp, (2) be mentored by an interdisciplinary team of experienced researchers, and (3) be immersed in the research and clinical environments of the Johns Hopkins Diabetes Center, the Welch Center for Epidemiology, Prevention and Clinical Research, the Johns Hopkins Exercise Physiology and Body Composition Core, the Johns Hopkins Center on Aging and Health, and intramural National Institute on Aging--Clinical Research Branch. This CDA will provide her with the skills she needs to become an independent investigator in accelerated muscle loss as a complication of type 2 diabetes. Building upon her prior experience in applying functional outcomes to diabetes research, she has developed a novel approach to understand and clinically assess the association of dysglycemia and/or IR with muscle loss that draws upon the fields of endocrinology, epidemiology, gerontology, and exercise physiology. In Aim 1, she will use two established datasets, one cross-sectional and one longitudinal, to identify clinical biomarkers of dysglycemia and indices of IR that predict decreased lower extremity muscle mass and strength. In Aim 2, she will determine the extent to which the ability of exercise to attenuate muscle loss in persons with diabetes depends upon the existing severity of dysglycemia or IR, in a trial comparing a 6 month exercise training intervention to a control condition. In Aim 3, she will recruit drug-naive adults with diabetes into a novel clinical study to investigate how an oral agent (pioglitazone) that improves peripheral insulin sensitivity, directly assessed with clamp, can effect changes in distinct but related aspects of skeletal muscle mitochondrial function--in vitro using percutaneous muscle biopsy and in vivo using 31P magnetic resonance spectroscopy-- versus placebo and whether effects differ by age. These findings should establish a framework to evaluate the ability of existing diabetes therapies to preserve muscle and potentially identify new therapeutic targets.